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Title: Subcellular distribution of cyclin-dependent kinase-like 5 (CDKL5) is regulated through phosphorylation by dual specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A)

Abstract

Cyclin-dependent kinase-like 5 (CDKL5) is a Ser/Thr protein kinase primarily expressed in the central nervous system and is known to cause X-linked neurodevelopmental disorders such as Rett syndrome. However, the mechanisms regulating CDKL5 have not yet been fully clarified. Therefore, in this study, we investigated the protein kinase that directly phosphorylates CDKL5, identifying it as dual specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A), an enzyme binding to and phosphorylating CDKL5. We showed that subcellular distribution of CDKL5 was regulated by its phosphorylation by DYRK1A. In mouse neuroblastoma Neuro2a cells, CDKL5 was localized in both the cytosol and nucleus, whereas DYRK1A showed a typical nuclear localization. When CDKL5 and DYRK1A were co-expressed, the cytosolic localization of CDKL5 was significantly increased. Results of site-directed mutagenesis revealed that the phosphorylation site was Ser-308, in the vicinity of the nuclear localization signal. A mutation mimicking the phosphorylated serine residue by aspartate substitution (S308D) changed CDKL5 localization to the cytosol, whereas the corresponding alanine-substituted analog, CDKL5(S308A), was primarily localized to the nucleus. Taken together, these results strongly suggested that DYRK1A bound to CDKL5 and phosphorylated it on Ser-308, thus interfering with its nuclear localization. - Highlights: • We investigated the mechanism regulating subcellular localization of CDKL5. •more » DYRK1A was identified as an enzyme that bound to and phosphorylated CDKL5. • The phosphorylation site of CDKL5 was Ser-308, in the vicinity of the NLS. • When DYRK1A was co-expressed, the cytosolic CDKL5 was significantly increased. • In conclusion, DYRK1A regulates CDKL5 localization via phosphorylation on Ser-308.« less

Authors:
 [1];  [1];  [2];  [3]; ;  [1];  [1]
  1. Department of Life Sciences, Faculty of Agriculture, Kagawa University, Kagawa, 761-0795 (Japan)
  2. (Japan)
  3. The Integrated Center for Mass Spectrometry, Graduate School of Medicine, Kobe University, Kobe, 650-0017 (Japan)
Publication Date:
OSTI Identifier:
22696750
Resource Type:
Journal Article
Resource Relation:
Journal Name: Biochemical and Biophysical Research Communications; Journal Volume: 482; Journal Issue: 2; Other Information: Copyright (c) 2016 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; CENTRAL NERVOUS SYSTEM; PHOSPHORYLATION; PHOSPHOTRANSFERASES; SPECIFICITY; SUBCELLULAR DISTRIBUTION

Citation Formats

Oi, Ami, Katayama, Syouichi, Department of Pharmacy, College of Pharmaceutical Sciences, Ritsumeikan University, Shiga, 525-8577, Hatano, Naoya, Sugiyama, Yasunori, Kameshita, Isamu, and Sueyoshi, Noriyuki. Subcellular distribution of cyclin-dependent kinase-like 5 (CDKL5) is regulated through phosphorylation by dual specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A). United States: N. p., 2017. Web. doi:10.1016/J.BBRC.2016.11.048.
Oi, Ami, Katayama, Syouichi, Department of Pharmacy, College of Pharmaceutical Sciences, Ritsumeikan University, Shiga, 525-8577, Hatano, Naoya, Sugiyama, Yasunori, Kameshita, Isamu, & Sueyoshi, Noriyuki. Subcellular distribution of cyclin-dependent kinase-like 5 (CDKL5) is regulated through phosphorylation by dual specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A). United States. doi:10.1016/J.BBRC.2016.11.048.
Oi, Ami, Katayama, Syouichi, Department of Pharmacy, College of Pharmaceutical Sciences, Ritsumeikan University, Shiga, 525-8577, Hatano, Naoya, Sugiyama, Yasunori, Kameshita, Isamu, and Sueyoshi, Noriyuki. Sun . "Subcellular distribution of cyclin-dependent kinase-like 5 (CDKL5) is regulated through phosphorylation by dual specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A)". United States. doi:10.1016/J.BBRC.2016.11.048.
@article{osti_22696750,
title = {Subcellular distribution of cyclin-dependent kinase-like 5 (CDKL5) is regulated through phosphorylation by dual specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A)},
author = {Oi, Ami and Katayama, Syouichi and Department of Pharmacy, College of Pharmaceutical Sciences, Ritsumeikan University, Shiga, 525-8577 and Hatano, Naoya and Sugiyama, Yasunori and Kameshita, Isamu and Sueyoshi, Noriyuki},
abstractNote = {Cyclin-dependent kinase-like 5 (CDKL5) is a Ser/Thr protein kinase primarily expressed in the central nervous system and is known to cause X-linked neurodevelopmental disorders such as Rett syndrome. However, the mechanisms regulating CDKL5 have not yet been fully clarified. Therefore, in this study, we investigated the protein kinase that directly phosphorylates CDKL5, identifying it as dual specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A), an enzyme binding to and phosphorylating CDKL5. We showed that subcellular distribution of CDKL5 was regulated by its phosphorylation by DYRK1A. In mouse neuroblastoma Neuro2a cells, CDKL5 was localized in both the cytosol and nucleus, whereas DYRK1A showed a typical nuclear localization. When CDKL5 and DYRK1A were co-expressed, the cytosolic localization of CDKL5 was significantly increased. Results of site-directed mutagenesis revealed that the phosphorylation site was Ser-308, in the vicinity of the nuclear localization signal. A mutation mimicking the phosphorylated serine residue by aspartate substitution (S308D) changed CDKL5 localization to the cytosol, whereas the corresponding alanine-substituted analog, CDKL5(S308A), was primarily localized to the nucleus. Taken together, these results strongly suggested that DYRK1A bound to CDKL5 and phosphorylated it on Ser-308, thus interfering with its nuclear localization. - Highlights: • We investigated the mechanism regulating subcellular localization of CDKL5. • DYRK1A was identified as an enzyme that bound to and phosphorylated CDKL5. • The phosphorylation site of CDKL5 was Ser-308, in the vicinity of the NLS. • When DYRK1A was co-expressed, the cytosolic CDKL5 was significantly increased. • In conclusion, DYRK1A regulates CDKL5 localization via phosphorylation on Ser-308.},
doi = {10.1016/J.BBRC.2016.11.048},
journal = {Biochemical and Biophysical Research Communications},
number = 2,
volume = 482,
place = {United States},
year = {Sun Jan 08 00:00:00 EST 2017},
month = {Sun Jan 08 00:00:00 EST 2017}
}